There are good reasons for believing that development of an effective vaccine against HIV-1 in humans is going to be a very difficult task. The predicted difficulty in achieving vaccine protection against HIV and SIV has more or less been borne out by vaccine trials in animal models. Our laboratory has recently demonstrated impressive protective effects of live-attenuated, nef-deleted and multiply-deleted derivatives of SIV as vaccines. No other vaccine approach that we have tried has come even remotely close to the protective effects that we have seen with the live- attenuated approach. Although we do not know the basis for the protection, continued antigen expression resulting from persistent infection may be a key factor. We will investigate whether persistent vectored expression resulting from herpesvirus infection can match the live-attenuated approach for protective efficacy. Replication competent strains of the alpha herpesvirus, herpes simplex virus, and the gamma herpesvirus, herpesvirus saimiri, that express SIV antigens will be tested for their ability to elicit protective efficacy in the SIV/rhesus monkey model. The properties of herpesviruses that utilize a constitutive SV promoter vs endogenous herpesviral promoters for vectored expression will be compared since a regulated herpesvirus promoter may be needed for high level persistence. We will also analyze the ability of replication- defective herpes simplex virus vector expressing SIV antigens and of replication-defective SIV to elicit immune responses and protection. The proposed studies are expected to provide basic information on the types of immunization and immune responses that are needed to achieve solid vaccine protection.